P-3: Radiation Inducible TNF-a Therapy for Prostate Cancer

高危局限性前列腺癌患者接受标准放疗和 雄激素消融是不可接受的。在放射治疗中加入放射增敏剂是有用的， 其他局部晚期癌症，如肺癌和直肠癌。TNF-α是一种有效的放射增敏剂， 抗肿瘤剂，但毒性限制了其作为全身药物的用途。Ad.Egr-TNF.11D（TNFeradeTM，GenVec， 盖瑟斯堡，MD）是复制缺陷型E1、E3、E4缺失腺病毒载体，其编码放射性- 人TNF-α cDNA上游的可诱导DNA序列。Ad.Egr-TNF. 11 D被激活 在放射后产生肿瘤内治疗水平的TNF-α和增强的肿瘤消退 通过血管破坏和血栓形成。为了在临床上发展这一概念， Ad.Egr-TNF. 11 D、放疗和雄激素消融，以确定联合治疗在这些患者中是否安全。 患者将进行。 人们认识到，添加诱导性局部TNF不太可能足以用于该人群， 需要探讨其他措施。此外，预测哪些患者最有可能 需要发展的利益。对于前者，TNF和辐射都能激活NF κ B， 可能对促进生存和抑制癌症和内皮细胞死亡至关重要， 成功的治疗。因此，将确定是否通过使用本发明的组合物抑制NFkB活化。 三萜类CDDO或腺病毒载体，其通过编码不可降解的（“超- IKBa（Ad.CMV.IkBa）的“阻遏物”形式进一步增强Ad.Egr-TNF. 11 D和放射治疗的活性 在临床前前列腺癌模型中。 最后，已经证明STAT 1是由辐射诱导的，并且初步证据表明， STAT 1的上调预示着对辐射的抵抗，提出了这样的假设，即基线水平的患者 升高的肿瘤STAT 1水平对标准放射的反应较差。因此，将确定STAT 1是否 和NFkB过表达与局部晚期前列腺增生的复发相关 癌症患者与预测的相关性将更强的患者接受放疗 比手术治疗的病人要多。

Outcomes for patients with high risk localized prostate cancer treated with standard radiotherapy and androgen ablation are unacceptable. The addition of radiation sensitizing agents to radiotherapy is useful in other locally advanced cancers such lung and rectal cancer. TNF-alpha is a potent radiosensitizing antitumor agent, but toxicity limits its use as a systemic drug. Ad.Egr-TNF.11D (TNFeradeTM, GenVec, Gaithersburg, MD) is a replication deficient E1, E3, E4 deleted adenoviral vector that encodes radio- inducible DNA sequences upstream from a cDNA for human TNF-alpha. Ad.Egr-TNF.11D is activated following radiation to produce intratumoral therapeutic levels of TNF-alpha and enhanced tumor regression via vascular destruction and thrombosis. To develop this concept clinically an early phase clinical trial of Ad.Egr-TNF.11D, radiotherapy, and androgen ablation to determine if the combination is safe in these patients will be conducted. It is recognized that addition of inducible local TNF is unlikely to be sufficient for this population and that additional measures need to be explored. Furthermore, markers for predicting whih patients are most likely to benefit need to be developed. In regards to the former, activation of NFkB by both TNF and radiation may be critical to promoting survival and inhibiting both the cancer and endothelial cell death required for successful treatment. Therefore, it will be determined if inhibition of NFkB activation through use of the triterpenoid CDDO or an adenoviral vector that inhibits NFkB by encoding a non-degradable ("super- repressor") form of IKBa (Ad.CMV.IkBa) further enhances the activity of Ad.Egr-TNF.11D and radiotherapy in preclinical prostate cancer models. Finally, it has been demonstrated that STAT1 is induced by radiation and preliminary evidence suggests that upregulation of STAT1 predicts for resistance to irradiation, raising the hypothesis that patients with baseline elevated tumor STAT1 levels will respond less well to standard radiation. It will thus be determined if STAT1 and NFkB overexpression are associated with recurrence in a historical group of locally advanced prostate cancer patients with the prediction that the association will be stronger in patients treated with radiotherapy than in patients treated with surgery.